Jia Yanhan, Wang Sheng, Urban Sylvia, Müller Judith M, Sum Manuela, Wang Qing, Bauer Helena, Schulte Uwe, Rampelt Heike, Pfanner Nikolaus, Schüle Katrin M, Imhof Axel, Forné Ignasi, Berlin Christopher, Sigle August, Gratzke Christian, Greschik Holger, Metzger Eric, Schüle Roland
Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany.
Nat Commun. 2025 Jan 30;16(1):1191. doi: 10.1038/s41467-025-56492-8.
Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.
前列腺癌（PCa）的生长依赖于由线粒体丙酮酸脱氢酶复合体（PDC）控制的从头脂肪生成。在本研究中，我们确定赖氨酸甲基转移酶（KMT）9是PDC活性的调节因子。KMT9定位于PCa细胞的线粒体中，但不存在于其他肿瘤细胞类型的线粒体中。线粒体KMT9通过其亚基二氢硫辛酰胺转乙酰基酶（DLAT）赖氨酸596位点的单甲基化来调节PDC活性。在体外和PCa小鼠模型中，KMT9的缺失均会损害PDC活性、从头脂肪生成和PCa细胞增殖。最后，在人类患者中，线粒体KMT9水平和DLAT K596me1与 Gleason分级相关。我们共同提出了一种PDC调节机制以及一个具有核和线粒体功能的组蛋白甲基转移酶的例子。PCa细胞对线粒体KMT9的依赖性使得开发选择性对抗PCa的治疗策略成为可能。
